Benzoic acid, benzoic acid derivatives and heteroaryl carboxylic acid conjugates of oxymorphone, prodrugs, methods of making and use thereof

ABSTRACT

The presently described technology provides compositions comprising aryl carboxylic acids and, for example NSAIDs, chemically conjugated to oxymorphone (4,5-α-epoxy-3,14-dihydroxy-17-methylmorphinan-6-one) to form novel prodrugs/compositions of oxymorphone, including benzoates, salicylates, propionates, fenamates, and acetates, which have a decreased potential for abuse of oxymorphone. The present technology also provides methods of treating patients, pharmaceutical kits and methods of synthesizing conjugates of the present technology.

RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.15/589,158, filed May 8, 2018, which is a divisional application of U.S.patent application Ser. No. 14/956,642, filed Dec. 2, 2015, which claimsthe priority of U.S. provisional application Ser. No. 62/086,326, filedDec. 2, 2014, which is incorporated by reference in its entirety.

FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT

[Not Applicable]

BACKGROUND OF THE INVENTION

Opioids are highly effective as analgesics and are commonly prescribedfor the treatment of acute and chronic pain. They are also commonly usedas antitussives. Opioids, however, also produce euphoria and can behighly addictive. As a result, they are often abused with far reachingsocial and health related consequences.

Because of the inherent potential for abuse, it is desirable that anypharmaceutical composition containing an opioid agonist be made asabuse-resistant or abuse-deterrent as practical. Illicit users oftenwill attempt, for example, to circumvent the extended release propertiesof conventional opioid dosage forms/products by injecting or otherwisemisusing or tampering with such dosage forms/products in order toachieve an immediate release of the opioid agonist.

Despite their addictive properties and the potential for abuse,morphine-like drugs, particularly, codeine, hydrocodone, oxycodone andoxymorphone have been routinely prescribed as treatment for moderate tosevere acute and chronic pain in recent decades. This is, in part,because there are currently no alternative therapies that treat severepain and do not produce a psychotropic effect other than, for example,the less potent non-steroidal anti-inflammatory drugs (NSAIDs) orcentral analgesics such as acetaminophen that are typically inadequateto treat severe pain. As a result, there is a need to decrease the abusepotential. Thus far, conventional approaches taken, unfortunately, havenot solved the abuse deterrent challenge.

Oxymorphone is a semi-synthetic opioid synthesized from poppy-derivedthebaine. It is a narcotic analgesic generally indicated for use inmanaging moderate to moderately severe acute or chronic pain. However,patients taking opioid analgesics such as oxymorphone for pain reliefcan become unintentionally addicted, for example, physically. Astolerance to the opioid develops, more drug is needed to alleviate thepain and generate the sense of well-being initially achieved with theprescribed dose. This leads to dose escalation, which if left uncheckedcan lead rapidly to addiction. In some cases, patients have become veryaddicted in as little as approximately thirty days. Thus, there is anongoing need and desire within the medical pain management community foran abuse-resistant or abuse-deterrent opioid product, such as anabuse-resistant or abuse-deterrent oxymorphone dosage form and/orproduct that continues to offer pain relief for moderate to moderatelysevere pain.

BRIEF SUMMARY OF THE INVENTION

The presently claimed technology utilizes, at least, covalentconjugation of the opioid oxymorphone with certain aryl carboxylic acidsto decrease its potential for causing overdose or abuse by requiring theactive oxymorphone to be released through enzymatic or metabolicbreakdown of the conjugate in vivo. Aryl carboxylic acids includecarboxylic acids that contain an aromatic ring structure. The presenttechnology also provides one or more methods of delivering oxymorphoneas conjugates that release the oxymorphone following oral administrationwhile being resistant to abuse by circuitous routes such as intravenous(“shooting”) injection and intranasal administration (“snorting”).

The presently described technology, in at least one aspect, provides aslow/sustained/controlled/extended release composition of conjugatedoxymorphone that allows slow/sustained/controlled/extended delivery ofthe oxymorphone, and/or any active metabolites, into the blood system ofa human or animal within a therapeutic window upon, for example, oraladministration. At least some compositions/formulations of the currentlyclaimed and described technology can lessen addiction/abuse potentialand/or other common side effects associated with oxymorphone and similaropioid compounds.

The presently described and claimed technology encompasses one or morecompositions having oxymorphone covalently attached to at least one arylcarboxylic acid, a derivative thereof, a salt thereof, or a combinationthereof. The at least one aryl carboxylic acid is covalently attached toeither the C-3 hydroxyl group of oxymorphone, the C-6 enol tautomer ofoxymorphone, the C-14 hydroxyl group of oxymorphone, or independentlyselected aryl carboxylic acids can be attached to a combination of theC-3 hydroxyl group of oxymorphone, the C-6 enol tautomer and/or the C-14hydroxyl groups of oxymorphone. The at least one aryl carboxylic acidcan be covalently attached to either the C-3 hydroxyl group ofoxymorphone, the C-6 enol tautomer of oxymorphone, or the C-14 hydroxylgroup of oxymorphone. Alternatively, at least two independently selectedaryl carboxylic acids can be attached to both the C-3 hydroxyl group andthe C-6 enol tautomer of oxymorphone, or the C-6 enol tautomer and C-14hydroxyl group of oxymorphone, or the C-3 hydroxyl group and C-14hydroxyl group of oxymorphone. Alternatively, at least threeindependently selected aryl carboxylic acids can be attached to the C-3hydroxyl group, C-6 enol tautomer and C-14 hydroxyl group ofoxymorphone.

In some embodiments, the aryl carboxylic acid is a benzoate having thefollowing structure:

wherein X, Y and Z are independently selected from the group consistingessentially of H, O, S, NH and —(CH₂)_(x)—; R¹, R² and R³ areindependently selected from the group consisting of H, alkyl, alkoxy,aryl, alkenyl, alkynyl, halo, haloalkyl, alkylaryl, arylalkyl,heterocycle, arylalkoxy, cycloalkyl, cycloalkenyl and cycloalkynyl; o,p, q are independently selected from about 0 or about 1; and x is aninteger between about 1 and about 10, such as about 1, about 2, about 3,about 4, about 5, about 6, about 7, about 8, about 9, and about 10.

In another aspect of the present disclosure, the aryl carboxylic acidcan be an aminobenzoate, an analog of anthranilic acid, fenamate,hydroxybenzoate, aminohydroxybenzoate, salicylic acid analog, orderivative thereof.

In other aspects of the present technology, the aryl carboxylic acid is,for example, benzoic acid, salicylic acid, acetylsalicylic acid(aspirin), 3-hydroxybenzoic acid, 4-hydroxybenzoic acid,6-methylsalicylic acid, o,m,p-cresotinic acid, anacardic acids,4,5-dimethylsalicylic acid, o,m,p-thymotic acid, diflusinal,o,m,p-anisic acid, 2,3-dihydroxybenzoic acid (2,3-DHB), α,β,γ-resorcylicacid, protocatechuic acid, gentisic acid, piperonylic acid,3-methoxysalicylic acid, 4-methoxysalicylic acid, 5-methoxysalicylicacid, 6-methoxysalicylic acid, 3-hydroxy-2-methoxybenzoic acid,4-hydroxy-2-methoxybenzoic acid, 5-hydroxy-2-methoxybenzoic acid,vanillic acid, isovanillic acid, 5-hydroxy-3-methoxybenzoic acid,2,3-dimethoxybenzoic acid, 2,4-dimethoxybenzoic acid,2,5-dimethoxybenzoic acid, 2,6-dimethoxybenzoic acid, veratric acid(3,4-dimethoxybenzoic acid), 3,5-dimethoxybenzoic acid, gallic acid,2,3,4-trihydroxybenzoic acid, 2,3,6-trihydroxybenzoic acid,2,4,5-trihydroxybenzoic acid, 3-O-methylgallic acid (3-OMGA),4-O-methylgallic acid (4-OMGA), 3,4-O-dimethylgallic acid, syringicacid, 3,4,5-trimethoxybenzoic acid, or derivatives thereof.

In still another aspect of the present technology, the aryl carboxylicacid can be an aminohydroxybenzoate selected from the group consistingessentially of 4-aminosalicylic acid, 3-hydroxyanthranilic acid,3-methoxyanthranilic acid, or derivatives thereof.

In another aspect of the present technology, the aryl carboxylic acid isan aminobenzoate can be selected from the group containing, for example,anthranilic acid, 3-aminobenzoic acid, 4,5-dimethylanthranilic acid,N-methylanthranilic acid, N-acetylanthranilic acid, fenamic acids (e.g.,tolfenamic acid, mefenamic acid, flufenamic acid), 2,4-diaminobenzoicacid (2,4-DABA), 2-acetylamino-4-aminobenzoic acid,4-acetylamino-2-aminobenzoic acid, 2,4-diacetylaminobenzoic acid, orderivatives thereof.

In a still further aspect of the present technology, the aryl carboxylicacid is a hydroxybenzoate. For example, the aryl carboxylic acid can besalicylic acid, acetylsalicylic acid (aspirin), 3-hydroxybenzoic acid,4-hydroxybenzoic acid, 6-methylsalicylic acid, o,m,p-cresotinic acid,anacardic acids, 4,5-dimethylsalicylic acid, o,m,p-thymotic acid,diflusinal, o,m,p-anisic acid, 2,3-dihydroxybenzoic acid (2,3-DHB),α,β,γ-resorcylic acid, protocatechuic acid, gentisic acid, piperonylicacid, 3-methoxysalicylic acid, 4-methoxysalicylic acid,5-methoxysalicylic acid, 6-methoxysalicylic acid,3-hydroxy-2-methoxybenzoic acid, 4-hydroxy-2-methoxybenzoic acid,5-hydroxy-2-methoxybenzoic acid, vanillic acid, isovanillic acid,5-hydroxy-3-methoxybenzoic acid, 2,3-dimethoxybenzoic acid,2,4-dimethoxybenzoic acid, 2,5-dimethoxybenzoic acid,2,6-dimethoxybenzoic acid, veratric acid (3,4-dimethoxybenzoic acid),3,5-dimethoxybenzoic acid, gallic acid, 2,3,4-trihydroxybenzoic acid,2,3,6-trihydroxybenzoic acid, 2,4,5-trihydroxybenzoic acid,3-O-methylgallic acid (3-OMGA), 4-O-methylgallic acid (4-OMGA),3,4-O-dimethylgallic acid, syringic acid, 3,4,5-trimethoxybenzoic acid,or derivatives thereof.

In a yet a further aspect of the present technology, the aryl carboxylicacid can be a heteroaryl carboxylic acid having one of the followingstructures:

wherein X, Y and Z can be independently any combination of H, O, S, NHor —(CH₂)_(x)—. R¹, R² and R³ can be independently any of the following:H, alkyl, alkoxy, aryl, alkenyl, alkynyl, halo, haloalkyl, alkylaryl,arylalkyl, heterocycle, arylalkoxy, cycloalkyl, cycloalkenyl orcycloalkynyl; o, p, q can be independently either about 0 or about 1;and x is an integer between about 1 and about 10, such as about 1, about2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, andabout 10.

In some aspects of the presently described and claimed technology, theheteroaryl carboxylic acid can be, for example, nicotinic acid (niacin),isonicotinic acid, picolinic acid, 3-hydroxypicolinic acid,6-hydroxynicotinic acid, citrazinic acid, 2,6-dihydroxynicotinic acid,kynurenic acid, xanthurenic acid, 6-hydroxykynurenic acid,8-methoxykynurenic acid, 7,8-dihydroxykynurenic acid,7,8-dihydro-7,8-dihydroxykynurenic acid, or derivatives thereof.

In additional aspects of the present disclosure, the aryl carboxylic canbe a derivative of phenylacetate having the following general structure:

wherein X, Y and Z can be independently any combination of H, O, S, NHor —(CH₂)_(x)—. R¹, R² and R³ can be independently any of the following:H, alkyl, alkoxy, aryl, alkenyl, alkynyl, halo, haloalkyl, alkylaryl,arylalkyl, heterocycle, arylalkoxy, cycloalkyl, cycloalkenyl orcycloalkynyl; o, p, q can be independently either about 0 or about 1;Alk is an alkyl chain —(CH₂)_(n)— with n being either about 0 or about1; and R⁶ can be H, OH or carbonyl.

In some aspects of the presently described and claimed technology, thearyl carboxylic can be 2-methyl-2-phenylacetic acid, at least oneNon-Steroidal Anti-Inflammatory Drug, a profen, a tyrosine metabolite,or derivatives thereof. Additionally, in further aspects of the presenttechnology, the aryl carboxylic acid can be phenylacetic acid(hydratropic acid), 2-hydroxyphenylacetic acid, 3-hydroxyphenylaceticacid, 4-hydroxyphenylacetic acid, homoprotocatechuic acid, homogentisicacid, 2,6-dihydroxyphenylacetic acid, homovanillic acid, homoisovanillicacid, homoveratric acid, atropic acid, d,l-tropic acid, diclofenac,d,l-mandelic acid, 3,4-dihydroxy-d,l-mandelic acid,vanillyl-d,l-mandelic acid, isovanillyl-d,l-mandelic acid, ibuprofen,fenoprofen, carprofen, flurbiprofen, ketoprofen, naproxen, orderivatives thereof.

In yet other aspects of the present technology, aryl carboxylic acid canbe an analog of cinnamic acid or phenylpropionic acid having one of thefollowing structures:

wherein X, Y and Z can be independently any combination of H, O, S, NHor —(CH₂)_(x)—; R¹, R² and R³ can be independently any of the following:H, alkyl, alkoxy, aryl, alkenyl, alkynyl, halo, haloalkyl, alkylaryl,arylalkyl, heterocycle, arylalkoxy, cycloalkyl, cycloalkenyl orcycloalkynyl; o, p, q can be independently either about 0 or about 1; R⁴is H or OH; and R⁵ is H, and OH or carbonyl.

In this particular aspect of the presently described and claimedtechnology, the aryl carboxylic acid can be cinnamic acid,o,m,p-coumaric acid, 2,3-dihydroxycinnamic acid, 2,6-dihydroxycinnamicacid, caffeic acid, ferulic acid, isoferulic acid, 5-hydroxyferulicacid, sinapic acid, 2-hydroxy-3-phenylpropenoic acid, or derivativesthereof.

In still further aspects of the present technology, the aryl carboxylicacid can also be a phenylpropionic acid or a substituted derivativethereof. In this aspect of the present technology, the aryl carboxylicacid can be, for example, phenylpropionic acid, melilotic acid,3-hydroxyphenylpropanoic acid, 4-hydroxyphenylpropanoic acid,2,3-dihydroxyphenylpropanoic acid, d,l-phenyllactic acid,o,m,p-hydroxy-d,l-phenyllactic acid, phenylpyruvic acid, or derivativesthereof.

In another aspect of the present technology, the aryl carboxylic acidcan be a phenylacetate or a substituted derivative thereof. In thisaspect of the present technology, the aryl carboxylic acid can be, forexample, phenylacetic acid (hydratropic acid), 2-hydroxyphenylaceticacid, 3-hydroxyphenylacetic acid, 4-hydroxyphenylacetic acid,homoprotocatechuic acid, homogentisic acid, 2,6-dihydroxyphenylaceticacid, homovanillic acid, homoisovanillic acid, homoveratric acid,atropic acid, d,l-tropic acid, diclofenac, d,l-mandelic acid,3,4-dihydroxy-d,l-mandelic acid, vanillyl-d,l-mandelic acid,isovanillyl-d,l-mandelic acid, ibuprofen, fenoprofen, carprofen,flurbiprofen, ketoprofen, naproxen, or derivatives thereof.

The presently described technology further encompasses at least onecomposition having oxymorphone covalently attached to at least onenonsteroidal anti-inflammatory drug (NSAID), a derivative thereof, asalt thereof, or a combination thereof. The at least one NSAID iscovalently attached to either the C-3 hydroxyl group of oxymorphone, theC-6 enol tautomer of oxymorphone, the C-14 hydroxyl group ofoxymorphone, or independently selected NSAIDs can be attached to acombination of the C-3 hydroxyl group of oxymorphone, the C-6 enoltautomer and/or the C-14 hydroxyl groups of oxymorphone. The at leastone NSAID can be covalently attached to either the C-3 hydroxyl group ofoxymorphone, the C-6 enol tautomer of oxymorphone, or the C-14 hydroxylgroup of oxymorphone. Alternatively, at least two independently selectedNSAIDs can be attached to both the C-3 hydroxyl group and the C-6 enoltautomer of oxymorphone, or the C-6 enol tautomer and C-14 hydroxylgroup of oxymorphone, or the C-3 hydroxyl group and C-14 hydroxyl groupof oxymorphone. Alternatively, at least three independently selectedNSAIDs can be attached to the C-3 hydroxyl group, C-6 enol tautomer andC-14 hydroxyl group of oxymorphone. The NSAID of this and other aspectsof the present disclosure can be, for example, a salicylate such asaspirin, diflusinal, or Salicylate. The NSAID can also be, for example,a propionate such as ibuprofen, dexibuprofen, naproxen, fenoprofen,ketoprofen, dexketoprofen, flurbiprofen, oxaprozin, or loxoprofen. TheNSAID can also be an acetate such as, for example, indomethacin,tolmetin, sulindac, etodolac, ketorolac, or diclofenac. The NSAID canalso be an oxicam such as, for example, piroxicam, meloxicam, tenoxicam,lornoxicam, or isoxicam. The NSAID can also be a fenamate such as, forexample, mefenamic acid, meclofenamic acid, flufenamic acid, ortolfenamic acid. The NSAID can also be a COX-2 inhibitor such as, forexample, celecoxib, valdecoxib, or lumiracoxib.

In yet another aspect, the present technology provides one or moreconjugates of oxymorphone for use to treat pain, preferably moderate tosevere pain, or for use to reduce or prevent oral, intranasal orintravenous drug abuse. In some aspects, the conjugates provide oral,intranasal or parenteral drug abuse resistance or deterrence.

In a further aspect, the present technology provides at least oneconjugate of oxymorphone that exhibits a slower rate of release overtime and a greater or equal AUC when compared to an equivalent molaramount of unconjugated oxymorphone over the same time period. In otheraspects, the conjugate of oxymorphone exhibits less variability in theoral PK profile when compared to unconjugated oxymorphone.

In yet another aspect, at least one conjugate has reduced side effectswhen compared with unconjugated oxymorphone or prevents drug tamperingby either physical or chemical manipulation.

In yet at still further aspect, at least one conjugate of the presentlydescribed and claimed technology is provided in an amount sufficient toprovide a therapeutically equivalent AUC when compared to an equivalentmolar amount of unconjugated oxymorphone. In additional aspects, atleast one conjugate of the present technology is provided in an amountsufficient to provide a therapeutically equivalent AUC when compared toan equivalent molar amount of unconjugated oxymorphone, but does notprovide a C_(max) spike, or, alternatively, has a lower C_(max) than atherapeutically equivalent amount of unconjugated oxymorphone. Inanother aspect, at least one conjugate is provided in an amountsufficient to provide a therapeutically equivalent AUC when compared toan equivalent molar amount of unconjugated oxymorphone, but does notprovide an equivalent C_(max) spike. In some additional aspects, atleast one conjugate of the present technology provides an equivalentC_(max) spike when compared to unconjugated oxymorphone.

In an additional aspect, the present technology provides at least onemethod for treating a patient (human or animal) having a disease,disorder or condition requiring or mediated by the binding of an opioidto the opioid receptors of the patient, comprising orally administeringto the patient a pharmaceutically or therapeutically effective amount ofat least one conjugate of oxymorphone disclosed and/or claimed herein.

In another aspect, the present technology provides a composition that isused to treat narcotic or opioid abuse; to prevent narcotic or opioidwithdrawal; to treat moderate to severe pain; to reduce or prevent oral,intranasal or intravenous drug abuse; or to provide oral, intranasal orparenteral drug abuse resistance.

In a still further aspect, the present technology provides at least onemethod for treating a patient (human or animal) having a disease,disorder or condition (such as pain) which can be treated by the bindingof at least one opioid to the opioid receptors of the patient, themethod comprising orally administering to the patient a therapeuticallyor pharmaceutically effective amount of at least one conjugate ofoxymorphone, a salt thereof, a derivative thereof or a combinationthereof.

In an additional aspect, the present technology provides at least onemethod for treating a patient (human or animal) having a disease,disorder or condition (such as addiction) which can be treated byinhibiting binding of at least one opioid to the opioid receptors of thepatient, comprising the step of orally administering to the patient atherapeutically or pharmaceutically effective amount of at least oneconjugate of oxymorphone disclosed and/or claimed herein.

In a yet further aspect, the present technology provides at least onepharmaceutical kit including a specified amount of individual doses in apackage containing a therapeutically or pharmaceutically effectiveamount of at least one conjugate of oxymorphone described and/or claimedherein. In some aspects, the kits of the presently described technologycan further include one or more instructions regarding use of the kit ina method or manner for treating or preventing drug withdrawal symptomsor pain in a human or animal patient.

BRIEF DESCRIPTION OF SEVERAL VIEWS OF THE DRAWINGS

FIG. 1 provides chemical structures of hydroxybenzoic acids and benzoicacid derivatives for use in the making of the conjugates of the presenttechnology.

FIG. 2 provides chemical structures of aminobenzoic acids for use in themaking of the conjugates of the present technology.

FIG. 3 provides chemical structures of aminohydroxybenzoic acids for usein the making of conjugates of the present technology.

FIG. 4 provides chemical structures of heteroaryl carboxylic acids foruse in the making of conjugates of the present technology.

FIG. 5 provides chemical structures of phenylacetates for use in themaking of conjugates of the present technology.

FIG. 6 provides chemical structures of phenylproprionates for use in themaking of conjugates of the present technology.

FIG. 7 provides chemical structures of cinnamates for use in the makingof conjugates of the present technology.

FIG. 8 provides chemical structures of NSAID salicylates for use in themaking of conjugates of the present technology.

FIG. 9 provides chemical structures of NSAID propionates for use in themaking of conjugates of the present technology.

FIG. 10 provides chemical structures of NSAID acetates for use in themaking of conjugates of the present technology.

FIG. 11 provides chemical structures of NSAID oxicams for use in themaking of conjugates of the present technology.

FIG. 12 provides chemical structures of NSAID fenamates for use in themaking of conjugates of the present technology.

FIG. 13 provides chemical structures of NSAID selective COX-2 inhibitorsfor use in the making of conjugates of the present technology.

FIG. 14 provides PK profile graph data for an oral rat study comparingoxymorphone plasma concentrations generated by oxymorphone, 6-Bz-OM, and3-Indomethacin-OM.

FIG. 15 provides PK profile graph data for an oral rat study comparingoxymorphone plasma concentrations generated by oxymorphone and3-Cinnamate-OM.

FIG. 16 provides PK profile graph data for an oral rat study comparingoxymorphone plasma concentrations generated by oxymorphone and3,6-(Cinnamate)₂-OM.

FIG. 17 provides PK profile graph data for an oral rat study comparingoxymorphone plasma concentrations generated by oxymorphone,3-(4-MeO-Bz)-OM, and 3-(2-OH-Bz)-OM.

FIG. 18 provides PK profile graph data for an oral rat study comparingoxymorphone plasma concentrations generated by oxymorphone,6-(2-OH-Bz)-OM, and 6-(4-OH-Bz)-OM.

FIG. 19 provides PK profile graph data for an oral rat study comparingoxymorphone plasma concentrations generated by oxymorphone and3-(4-OH-Bz)-OM.

FIG. 20 provides PK profile graph data for an oral rat study comparingoxymorphone plasma concentrations generated by oxymorphone,3-Vanillate-OM, and 6-Vanillate-OM.

FIG. 21 provides PK profile graph data for an oral rat study comparingoxymorphone plasma concentrations generated by oxymorphone,6-(4-OH-Bz)-OM, and 3,6-(4-MeO-Bz)₂-OM.

FIG. 22 provides PK profile graph data for an oral rat study comparingoxymorphone plasma concentrations generated by oxymorphone, 6-(3-ABz)-OMand 6-(Cinnamate)-OM.

FIG. 23 provides PK profile graph data for an oral rat study comparingoxymorphone plasma concentrations generated by oxymorphone,3-(2-OAc-Bz)-OM and 3-Ketoprofen-OM.

FIG. 24 provides PK profile graph data for an oral rat study comparingoxymorphone plasma concentrations generated by oxymorphone and3-Fenoprofen-OM.

FIG. 25 provides PK profile graph data for an oral rat study comparingoxymorphone plasma concentrations generated by oxymorphone,3-Diflunisal-OM, and 6-Ketoprofen-OM.

FIG. 26 provides PK profile graph data for an intranasal rat studycomparing oxymorphone plasma concentrations generated by oxymorphone,6-Bz-OM, and 3-(4-MeO-Bz)-OM.

FIG. 27 provides PK profile graph data for an intranasal rat studycomparing oxymorphone plasma concentrations generated by oxymorphone,3-(2-OH-Bz)-OM, and 4-OH-Bz-OM.

FIG. 28 provides PK profile graph data for an intranasal rat studycomparing oxymorphone plasma concentrations generated by oxymorphone,3-Diflunisal-OM, and 6-Diflunisal-OM.

FIG. 29 provides PK profile graph data for an intranasal rat studycomparing oxymorphone plasma concentrations generated by oxymorphone and3,6-(4-MeO-Bz)₂-OM.

FIG. 30 provides PK profile graph data for an oral rat study comparingplasma concentrations generated by Bz-HC, 3-Bz-OM, 3,6-di-Bz-OM, and3,6,14-tri-Bz-OM.

FIG. 31 provides PK profile graph data for an oral rat study comparingplasma concentrations generated by 4-MeO-Bz-HC, 3-(4-MeO-Bz)-OM, and3,6,14-tri-(4-MeO-Bz)-OM.

FIG. 32 provides PK profile graph data for an oral rat study comparingplasma concentrations generated by Cinnamate-HC, 3,6-di-Cinnamate-OM,and 3,6,14-tri-Cinnamate-OM.

FIG. 33 provides PK profile graph data for an oral rat study comparingplasma concentrations generated by 3,6-di-(4-MeO-Bz)-HM and3,6-di-(4-MeO-Bz)-OM.

FIG. 34 provides PK profile graph data for an oral rat study comparingplasma concentrations generated by 6-(4-MeO-Bz)-HM and 6-(4-MeO-Bz)-OM.

FIG. 35 provides PK profile graph data for an oral rat study comparingplasma concentrations generated by 14-Bz-OC and 6-Bz-OM.

FIG. 36 provides PK profile graph data for an oral rat study comparingplasma concentrations generated by 6,14-di-(4-MeO-Bz)-OC and3,6-di-(4-MeO-Bz)-OM.

FIG. 37 provides PK profile graph data for an oral rat study comparingplasma concentrations generated by 6,14-di-Cinnamate-OC and3,6-di-Cinnamate-OM.

FIG. 38 provides PK profile graph data for an oral rat study comparingplasma concentrations generated by 6-ibuprofen-OC and 6-ibuprofen-OM.

DETAILED DESCRIPTION OF THE INVENTION

The present technology provides one or more compositions comprising arylcarboxylic acids chemically conjugated to oxymorphone(4,5-α-epoxy-3,14-dihydroxy-17-methylmorphinan-6-one) to form novelconjugates and/or prodrugs and/or compositions of oxymorphone. In someembodiments, the chemical bond between these two moieties can beestablished by reacting the carboxylic acid function of an arylcarboxylic acid with one of the following functional groups ofoxymorphone: C-3 hydroxyl group of oxymorphone, C-6 enol tautomer ofoxymorphone; C-14 hydroxyl of oxymorphone; or a combination of the C-3hydroxyl group of oxymorphone, the C-14 hydroxyl and/or the C-6 enoltautomer of oxymorphone.

The use of “oxymorphone” is meant to include, for example, asemisynthetic narcotic analgesic and antitussive prepared from codeinewith multiple actions qualitatively similar to those of codeine. It iscommonly used for the relief of moderate to moderately severe pain.Trade names include, for example, Opana®, Opana ER®, Numorphone® andNumorphan®. Salt forms of oxymorphone, such as oxymorphonehydrochloride, are encompassed by and envisaged within the practice andscope of the presently described and claimed technology.

Aryl carboxylic acids may be grouped into various categories andsubcategories. The carboxyl group of the present technology can beattached directly to the aromatic ring or be separated by an alkyl oralkenyl chain. The chain length of the alkyl or alkenyl group of thepresent technology does not generally exceed two unbranched carbons, butis not limited in the numbers of atoms on potential side-chains oradditional functional groups. The present technology includes bothcarbon only aryl and aryl groups with heteroatoms (heteroaryl). The arylor heteroaryl group of the present technology, which can be connecteddirectly or through an alkyl or alkenyl chain to the carboxyl function,may be a 6-membered ring and can contain no or one heteroatom. It shouldbe appreciated by those skilled in the relevant art that additionalsubstituted or unsubstituted aromatic or aliphatic rings may be fused tothis 6-membered aryl or heteroaryl moiety. The aryl carboxylic acids ofthe present technology preferably have only one free carboxylic acidgroup and the total number of phenyl substituents on the 6-membered ringshould be four or less.

The aryl carboxylic acids of the presently described and claimedtechnology may be grouped, without limitation, into one of three maincategories of compounds: (1) compounds wherein the carboxylic acid groupis directly attached to the aryl moiety; (2) compounds wherein thecarboxylic acid group is separated by one carbon from the aryl moiety;and (3) compounds wherein the carboxylic acid group is separated by twocarbons from the aryl moiety.

Some embodiments of the present technology provide carboxylic acidsconjugated to oxymorphone, where the carboxylic acid group is directlyattached to the aryl moiety. Carboxylic acids directly attached to thearyl moiety include, for example, benzoates and heteroaryl carboxylicacids.

Some embodiments of the present technology provide at least oneconjugate of oxymorphone and at least one benzoic acid or benzoic acidderivative, a salt thereof, or a combination thereof. Benzoates arecommon in nature and include, for example, but are not limited to,aminobenzoates (e.g., anthranilic acid analogs such as fenamates),aminohydroxybenzoates and hydroxybenzoates (e.g., salicylic acidanalogs).

The general structure of benzoates of the present technology is:

wherein X, Y and Z can be independently any combination of H, O, S, NHor —(CH₂)_(x)—; R¹, R² and R³ can be independently any of the following:H, alkyl, alkoxy, aryl, alkenyl, alkynyl, halo, haloalkyl, alkylaryl,arylalkyl, heterocycle, arylalkoxy, cycloalkyl, cycloalkenyl orcycloalkynyl; o, p, q can be independently either about 0 or about 1;and x is an integer between about 1 and about 10, such as about 1, about2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, andabout 10.

In yet additional embodiments, the present technology provides at leastone prodrug or composition comprising at least one conjugate ofoxymorphone and at least one heteroaryl carboxylic acid, a derivativethereof, or a combination thereof. The heteroaryl carboxylic acid can beselected from formula II, formula III or formula IV where formula II,formula III and formula IV are:

wherein X, Y and Z can be independently any combination of H, O, S, NHor —(CH₂)_(x)—. R¹, R² and R³ can be independently any of the following:H, alkyl, alkoxy, aryl, alkenyl, alkynyl, halo, haloalkyl, alkylaryl,arylalkyl, heterocycle, arylalkoxy, cycloalkyl, cycloalkenyl orcycloalkynyl. o, p, q can be independently either about 0 or about 1. xis an integer between about 1 and about 10, such as about 1, about 2,about 3, about 4, about 5, about 6, about 7, about 8, about 9, and about10.

Aryl carboxylic acids with one carbon atom between aromatic ring andcarboxyl group of the present technology in some embodiments have thefollowing general structure:

wherein X, Y and Z can be independently any combination of H, O, S, NHor —(CH₂)_(x)—. R¹, R² and R³ can be independently any of the following:H, alkyl, alkoxy, aryl, alkenyl, alkynyl, halo, haloalkyl, alkylaryl,arylalkyl, heterocycle, arylalkoxy, cycloalkyl, cycloalkenyl orcycloalkynyl. o, p, q can be independently either 0 or 1. Alk is analkyl chain —(CH₂)_(n)— with n being either 0 or 1. R⁶ can be H, OH orcarbonyl.

Aryl carboxylic acids with the carboxyl group separated by two carbonatoms from the aryl moiety of the present technology have the followinggeneral formula:

wherein X, Y and Z can be independently any combination of H, O, S, NHor —(CH₂)_(x)—. R¹, R² and R³ can be independently any of the following:H, alkyl, alkoxy, aryl, alkenyl, alkynyl, halo, haloalkyl, alkylaryl,arylalkyl, heterocycle, arylalkoxy, cycloalkyl, cycloalkenyl orcycloalkynyl. o, p, q can be independently either 0 or 1. R⁴ is H or OH;and R⁵ is H, OH or carbonyl.

Suitable hydroxybenzoic acids (hydroxybenzoates) can be found in FIG. 1and include, but are not limited to, benzoic acid, salicylic acid,acetylsalicylic acid (aspirin), 3-hydroxybenzoic acid, 4-hydroxybenzoicacid, 6-methylsalicylic acid, o,m,p-cresotinic acid, anacardic acids,4,5-dimethylsalicylic acid, o,m,p-thymotic acid, diflusinal,o,m,p-anisic acid, 2,3-dihydroxybenzoic acid (2,3-DHB), α,β,γ-resorcylicacid, protocatechuic acid, gentisic acid, piperonylic acid,3-methoxysalicylic acid, 4-methoxysalicylic acid, 5-methoxysalicylicacid, 6-methoxysalicylic acid, 3-hydroxy-2-methoxybenzoic acid,4-hydroxy-2-methoxybenzoic acid, 5-hydroxy-2-methoxybenzoic acid,vanillic acid, isovanillic acid, 5-hydroxy-3-methoxybenzoic acid,2,3-dimethoxybenzoic acid, 2,4-dimethoxybenzoic acid,2,5-dimethoxybenzoic acid, 2,6-dimethoxybenzoic acid, veratric acid(3,4-dimethoxybenzoic acid), 3,5-dimethoxybenzoic acid, gallic acid,2,3,4-trihydroxybenzoic acid, 2,3,6-trihydroxybenzoic acid,2,4,5-trihydroxybenzoic acid, 3-O-methylgallic acid (3-OMGA),4-O-methylgallic acid (4-OMGA), 3,4-O-dimethylgallic acid, syringicacid, 3,4,5-trimethoxybenzoic acid, or derivatives thereof.

Suitable aminobenzoic acids (aminobenzoates) are shown in FIG. 2 andinclude, but are not limited to, anthranilic acid, 3-aminobenzoic acid,4,5-dimethylanthranilic acid, N-methylanthranilic acid,N-acetylanthranilic acid, fenamic acids (e.g., tolfenamic acid,mefenamic acid, flufenamic acid), 2,4-diaminobenzoic acid (2,4-DABA),2-acetylamino-4-aminobenzoic acid, 4-acetylamino-2-aminobenzoic acid,2,4-diacetylaminobenzoic acid, or derivatives thereof.

Examples of suitable aminohydroxybenzoic acids that can be used in thepractice of the present technology are shown in FIG. 3. These include,but are not limited to, 4-aminosalicylic acid, 3-hydroxyanthranilicacid, or 3-methoxyanthranilic acid.

Suitable examples of heteroaryl carboxylic acids include, withoutlimitation, pyridine derivatives, some of which play an important rolein the nicotinate and tryptophan metabolism. In these compounds, onecarbon of the phenyl ring is replaced by a nitrogen atom. Besides thecarboxyl group, this set of compounds can have up to three additionalsubstituents, preferably but not limited to hydroxyl groups.

Examples of suitable heteroaryl carboxylic acids are shown in FIG. 4 andincluded, but are not limited to, Nicotinic acid (niacin), isonicotinicacid, picolinic acid, 3-hydroxypicolinic acid, 6-hydroxynicotinic acid,citrazinic acid, 2,6-dihydroxynicotinic acid, kynurenic acid,xanthurenic acid, 6-hydroxykynurenic acid, 8-methoxykynurenic acid,7,8-dihydroxykynurenic acid, 7,8-dihydro-7,8-dihydroxykynurenic acid, orderivatives thereof.

In some embodiments, the compositions of the presently described andclaimed technology can include a benzoate conjugate comprising at leastone oxymorphone conjugated to at least one benzoic acid or benzoic acidderivative, salt thereof or combination thereof.

In further embodiments, the benzoates can include numerous benzoic acidanalogs, benzoate derivatives with hydroxyl or amino groups or acombination of both. The hydroxyl and amino functions may be present intheir free form or capped with another chemical moiety, preferably butnot limited to methyl or acetyl groups. The phenyl ring may haveadditional substituents, but the total number of substituents can befour or less, three or less, or two or less.

In some embodiments, the carboxy group of the aryl carboxylic acids canbe attached directly to the aromatic ring. The present technologyincludes both carbon-only aryl groups and aryl groups with heteroatoms(heteroaryl). The aryl or heteroaryl group which is connected directlyto the carboxyl function can be a 6-membered ring and contains no or oneheteroatom. In various embodiments, the additional substituted orunsubstituted aromatic or aliphatic rings can be fused to this6-membered aryl or heteroaryl moiety. In further embodiments, the arylcarboxylic acids may have only one free carboxylic acid group and thetotal number of phenyl substituents on the 6-membered ring should befour or less, for example, about 4, about 3, about 2 or about 1.

In still further embodiments of the present technology, depending on theindividual aryl carboxylic acid that is connected to oxymorphone, theconjugate of oxymorphone can have a neutral, free acid, free base, orvarious pharmaceutically acceptable anionic or cationic salt forms orsalt mixtures with any ratio between positive and negative components.These salt forms include, but are not limited to: acetate, 1-aspartate,besylate, bicarbonate, carbonate, d-camsylate, l-camsylate, citrate,edisylate, formate, fumarate, gluconate, hydrobromide/bromide,hydrochloride/chloride, d-lactate, l-lactate, d,l-lactate, d,l-malate,l-malate, mesylate, pamoate, phosphate, succinate, sulfate, bisulfate,d-tartrate, l-tartrate, d,l-tartrate, meso-tartrate, benzoate,gluceptate, d-glucuronate, hybenzate, isethionate, malonate,methylsufate, 2-napsylate, nicotinate, nitrate, orotate, stearate,tosylate, thiocyanate, acefyllinate, aceturate, aminosalicylate,ascorbate, borate, butyrate, camphorate, camphocarbonate, decanoate,hexanoate, cholate, cypionate, dichloroacetate, edentate, ethyl sulfate,furate, fusidate, galactarate (mucate), galacturonate, gallate,gentisate, glutamate, glutamate, glutarate, glycerophosphate, heptanoate(enanthate), hydroxybenzoate, hippurate, phenylpropionate, iodide,xinafoate, lactobionate, laurate, maleate, mandelate, methanesufonate,myristate, napadisilate, oleate, oxalate, palmitate, picrate, pivalate,propionate, pyrophosphate, salicylate, salicylsulfate, sulfosalicylate,tannate, terephthalate, thiosalicylate, tribrophenate, valerate,valproate, adipate, 4-acetamidobenzoate, camsylate, octanoate, estolate,esylate, glycolate, thiocyanate, undecylenate, sodium, potassium,calcium, magnesium, zinc, aluminium, lithium, cholinate, lysinium,ammonium, tromethamine, or derivatives thereof.

Some embodiments of the present technology provide aryl carboxylic acidsconjugated to oxymorphone, where the carboxylic acid group is separatedby one carbon from the aryl moiety. Aryl carboxylic acids in thiscategory can include, without limitation, branched phenylpropionic acids(i.e., 2-methyl-2-phenylacetates) or other derivatives of phenylacetate.Examples of these compounds are certain types of NSAIDs (Non-SteroidalAnti-Inflammatory Drugs), such as profens, or tyrosine metabolites.

Examples of phenylacetates for use in the practice of the presenttechnology are shown in FIG. 5 and include, without limitation,phenylacetic acid (hydratropic acid), 2-hydroxyphenylacetic acid,3-hydroxyphenylacetic acid, 4-hydroxyphenylacetic acid,homoprotocatechuic acid, homogentisic acid, 2,6-dihydroxyphenylaceticacid, homovanillic acid, homoisovanillic acid, homoveratric acid,atropic acid, d,l-tropic acid, diclofenac, d,l-mandelic acid,3,4-dihydroxy-d,l-mandelic acid, vanillyl-d,l-mandelic acid,isovanillyl-d,l-mandelic acid, ibuprofen, fenoprofen, carprofen,flurbiprofen, ketoprofen, or naproxen.

Some embodiments of the present technology provide aryl carboxylic acidsconjugated to oxymorphone, wherein the carboxylic acid group isseparated by two carbons from the aryl moiety. This category of arylcarboxylic acids includes, without limitation, phenylpropionic acids andsubstituted derivatives thereof and analogs of cinnamic acid. Thesecompounds are abundant in nature in the form of natural products ormetabolites (e.g., phenylalanine metabolism).

Phenylpropionic acids have an ethylene group between the carboxylfunction and the phenyl ring. Both, the alkyl chain and the aryl moiety,can have substituents, such as, for example, hydroxyl groups. Somecompounds of this class can be found in the phenylalanine metabolism.

Examples of phenylpropionic acids that can be used in the practice ofthe present technology are shown in FIG. 6 and include, withoutlimitation, phenylpropionic acid, melilotic acid,3-hydroxyphenylpropanoic acid, 4-hydroxyphenylpropanoic acid,2,3-dihydroxyphenylpropanoic acid, d,l-phenyllactic acid,o,m,p-hydroxy-d,l-phenyllactic acid, phenylpyruvic acid, or derivativesthereof.

Cinnamic acids (3-phenylacrylic acids) are unsaturated analogs ofphenylpropionic acids. Cinnamates occur in two isomeric forms: cis (Z)and trans (E). The isomers of this invention are not limited to but arepreferably in the trans configuration. Similar to phenylpropionic acids,derivatives of cinnamic acid can be substituted on the alkenyl or arylmoiety of the molecule. Preferred substituents are hydroxyl and methoxygroups. Certain cinnamates play a key role in the phenylalaninemetabolism.

Examples of cinnamates that can be used in the practice of the presenttechnology are shown in FIG. 7 and include, without limitation, Cinnamicacid, o,m,p-coumaric acid, 2,3-dihydroxycinnamic acid,2,6-dihydroxycinnamic acid, caffeic acid, ferulic acid, isoferulic acid,5-hydroxyferulic acid, sinapic acid, 2-hydroxy-3-phenylpropenoic acid,or derivatives thereof.

Some embodiments of the present technology provide at least onecomposition having oxymorphone covalently attached to at least onenonsteroidal anti-inflammatory drug (NSAID), a derivative thereof, asalt thereof, or a combination thereof. The at least one NSAID iscovalently attached to either the C-3 hydroxyl group of oxymorphone, theC-6 enol tautomer of oxymorphone, or the C-14 hydroxyl group ofoxymorphone. Alternatively, independently selected aryl carboxylic acidsare attached to all or a combination of the C-3 hydroxyl group ofoxymorphone, the C-6 and/or the C-14 hydroxyl group of oxymorphone. TheNSAID can be, for example, a salicylate such as aspirin, diflusinal, orsalicylate (see, e.g., FIG. 8). The NSAID can also be, for example, aproprionate such as ibuprofen, dexibuprofen, naproxen, fenoprofen,ketoprofen, dexketoprofen, flurbiprofen, oxaprozin, loxoprofen, orderivatives thereof (see, e.g., FIG. 9). The NSAID can also be anacetate such as, for example, indomethacin, tolmetin, sulindac,etodolac, ketorolac, diclofenac, or derivatives thereof (see, e.g., FIG.10). The NSAID can be an oxicam such as, for example, piroxicam,meloxicam, tenoxicam, lornoxicam, isoxicam, or derivatives thereof (see,e.g., FIG. 11). The NSAID can also be a fenamate such as, for example,mefenamic acid, meclofenamic acid, or flufenamic acid, tolfenamic acid,or derivatives thereof (see, e.g., FIG. 12). The NSAID can also be aCOX-2 inhibitor such as, for example, celecoxib, valdecoxib,lumiracoxib, or derivatives thereof (see, e.g., FIG. 13).

Some embodiments of the present technology provide at least oneconjugate of oxymorphone that is broken down in vivo eitherenzymatically or chemically when administered via the intended route,releasing the active oxymorphone and the respective aryl carboxylic acidor metabolites thereof. The aryl carboxylic acids used in the conjugatesof the present technology are preferably non-toxic at the given dosinglevels and are preferably known drugs, natural products, metabolites, orGRAS (Generally Recognized As Safe) compounds (e.g., preservatives,dyes, flavors, etc.) or non-toxic mimetics thereof, including natural,synthetic, or both.

Compounds, conjugates, products, prodrugs, compositions and methods ofthe present technology provide, for example, reduced potential foroverdose, reduced potential for abuse or addiction and/or improveoxymorphone's characteristics with regard to side effect profiles orsuboptimal release profiles. Without wishing to be limited to the belowtheory, it is believed that the presently described and claimedtechnology provides abuse resistance via intranasal and intravenousroutes, because the described and claimed conjugates, compounds,compositions, prodrugs, and/or products are exposed to different enzymesand/or metabolic pathways upon oral administration where the conjugates,compounds, compositions, products and/or prodrugs are exposed to enzymesin the gut and first-pass metabolism as opposed to exposure to enzymesin the circulation or mucosal membranes which limits the ability of theoxymorphone from being released from the conjugate. Therefore, abuseresistance and/or abuse deterrence is provided by limiting the “rush” or“high” available from the active oxymorphone released by the prodrug,product, composition, compound, and/or conjugate of the presenttechnology and limiting the effectiveness of alternative routes ofadministration.

The compositions of the present technology preferably have no or asubstantially decreased pharmacological activity when administeredthrough injection or intranasal routes of administration. However, theyremain orally bioavailable. Again, not wanting to be bound by anyparticular theory, the bioavailability of the compositions of thepresent technology can be a result of the hydrolysis of the chemicallinkage (i.e., a covalent linkage) following oral administration. In atleast one embodiment of the present technology, release of oxymorphoneis delayed, reduced or prevented when the composition, compound,conjugate, product, or prodrug of the present technology is delivered,for example, by parenteral routes.

For example, in at least one embodiment, the composition of the presenttechnology maintains its effectiveness and abuse resistance and/ordeterrence following the crushing of the tablet, capsule or other oraldosage form. In contrast, from non-conjugated (or “unconjugated”)formulations of oxymorphone, the oxymorphone is released immediatelyfollowing crushing allowing the content of the crushed tablet to be usedby injection or snorting, in turn, producing the “rush” effect sought byaddicts.

In other embodiments of the present technology, the conjugates ofoxymorphone can be given orally to an animal or human patient, and, uponadministration, release the active oxymorphone by being hydrolyzed inthe body. Not to be bound by any particular theory, it is believed thatsince the aryl carboxylic acids are naturally occurring metabolites ormimetics thereof or pharmaceutically active compounds, these conjugatescan be easily recognized by physiological systems resulting inhydrolysis and release of oxymorphone. The conjugates themselves haveeither no or limited pharmacological activity as a conjugate andconsequently may follow a metabolic pathway that differs from the parentdrug.

In some embodiments of the present technology, the choice of a suitablearyl carboxylic acid (“ligands”) to conjugate to oxymorphone determinesthe release of oxymorphone into the systemic circulation and can becontrolled even when the conjugate is administered via routes other thanoral. In one embodiment, the modified oxymorphone would releaseoxymorphone similar to free or unmodified oxymorphone when administeredorally. In another embodiment, the conjugated oxymorphone releasesoxymorphone in a controlled, extended or sustained form or manner whenadministered orally. In further embodiments, thiscontrolled/sustained/extended release can alleviate certain side-effectsand improve upon the safety profile, or the abuse profile, or both ofthe parent drug. These side-effects may include, but are not limited to,anxiety, bruising, constipation, decreased appetite, difficultybreathing, dizziness, drowsiness, dry throat, dry mouth, lethargy,somnolence, pruritus, diarrhea, headache, nausea, stomach cramps,stomach pain, abdominal pain, dyspepsia, gastritis, chills, fever,anorexia, twitching, abnormal dreams, confusion, dysphoria, euphoria,insomnia, nervousness, thought abnormalities, dyspnea, hiccups, rash,hypotension, lymphadenopathy, tinnitus, abnormal vision, dysphagia,eructation, flatulence, gastrointestinal disorder, increased appetite,stomatitis, withdrawal symptom, seizures, edema, peripheral edema,thirst, malaise, chest pain, facial edema, ST depression, dehydration,syncope, migraine, abnormal gait, amnesia, hyperkinesia, hypesthesia,hypotonia, paresthesia, speech disorder, stupor, tremor, vertigo, tasteperversion, depression, agitation, depersonalization, emotionallability, hallucination, dysuria, hematuria, polyuria, urinaryretention, impotence, cough increased, voice alteration, dry skin,exfoliative dermatitis, abuse, addiction, amenorrhea, cholestasis,death, dental caries, increased hepatic enzymes, hyperalgesia,hypogonadism, hyponatremia, ileus, muscular hypertonia, overdose,palpitations, syndrome of inappropriate antidiuretic hormone secretion,urticarial, anaphylaxis, or vomiting. In yet another embodiment, theconjugated oxymorphone would selectively allow oxymorphone to bemetabolized to oxymorphone. In some embodiments, these conjugates can beused for pain relief, such as moderate to severe pain relief yet in anabuse resistance or deterrent manner and with the further potential ofreduced or prevented side effects of the parent drug or the metabolitethereof.

Oxymorphone and other opioids are also highly addictive and prone toabuse. Recreational drug abuse of opioids is a common problem andusually begins with oral doses taken with the purpose of achievingeuphoria (“rush” or “high”). Over time the drug abuser often increasesthe oral dosages to attain more powerful “highs” or to compensate forheightened opioid tolerance. This behavior can escalate and result inexploring other routes of administration such as intranasal (“snorting”)and intravenous (“shooting”).

In some embodiments of the present technology, the oxymorphone that isconjugated with a suitable aryl carboxylic acid ligand does not resultin rapid spikes in plasma concentrations after oral administration thatis sought by a potential drug abuser. In other embodiments, oxymorphonereleased from these conjugates has a delayed T_(max) and possibly lowerC_(max) than the unconjugated oxymorphone. Not to be bound by anyparticular theory, it is believed that the conjugates of the presenttechnology, when taken orally or by other non-oral routes, do notprovide the feeling of a “rush” even when taken at higher doses, butstill initially provide and/or maintain pain relief.

Additionally, in some embodiments, oxymorphone conjugated withappropriate ligands of the present technology is not hydrolyzedefficiently when administered via non-oral routes. As a result, theseconjugates do not generate high plasma or blood concentrations ofreleased oxymorphone when injected or snorted as compared to freeoxymorphone administered through these same routes.

In further embodiments, the conjugates of the present technology, sincethey consist of covalently bound oxymorphone, are not able to bephysically manipulated to release the oxymorphone opioid from theconjugated oxymorphone by various methods, for example, by grinding orcrushing solid dosage forms. Moreover, the conjugates of the presenttechnology exhibit resistance to chemical hydrolysis under conditions apotential drug abuser may apply to “extract” the active portion of themolecule, for example, by boiling, or acidic or basic solution treatmentof the conjugate. Such resistance offers significant advantages overconventional dosage forms and products of oxymorphone.

The compositions, compounds, conjugates and prodrugs of the presenttechnology can be oral dosage forms. These dosage forms include, but arenot limited to tablet, capsule, caplet, troche, lozenge, powder,suspension, syrup, solution, or oral thin film (OTF) dosage forms.Preferred oral administration forms are capsule, tablet, solutions andOTF dosage forms.

Solid dosage forms can include, but are not limited to, the followingtypes of excipients: anti-adherents, binders, coatings, disintegrants,fillers, flavors, dyes, colors, glidants, lubricants, preservatives,sorbents, sweeteners, derivatives thereof, or combinations thereof.

Oral formulations of the present technology can also be included in asolution or a suspension in an aqueous liquid or a non-aqueous liquid.The formulation can be an emulsion, such as an oil-in-water liquidemulsion or a water-in-oil liquid emulsion. The oils can be administeredby adding the purified and sterilized liquids to a prepared enteralformula, which is then placed in the feeding tube of a patient who isunable to swallow, for example.

Soft gel or soft gelatin capsules may be prepared, for example, bydispersing the formulation in an appropriate vehicle (vegetable oils arecommonly used) to form a high viscosity mixture. This mixture is thenencapsulated with a gelatin-based film using technology and machineryknown to those in the soft gel industry. The individual units so formedare then dried to constant weight as a final product for administrationto a human or animal patient.

Chewable tablets, for example, may be prepared by mixing the compounds,compositions, conjugates, prodrugs, or formulations of the presenttechnology with excipients designed to form a relatively soft, flavored,tablet dosage form that is intended to be chewed rather than swallowed.Conventional tablet machinery and procedures, for example, directcompression and granulation, i.e., or slugging, before compression, canbe utilized. Those individuals involved in pharmaceutical solid dosageform production are versed in the processes and the machinery used, asthe chewable dosage form is a very common dosage form in thepharmaceutical industry.

Film coated tablets, for example, may be prepared by coating tabletsusing techniques such as rotating pan coating methods or air suspensionmethods to deposit a contiguous film layer on a tablet containing thecompounds, conjugates, compositions, prodrugs or formulations of thepresent technology.

Compressed tablets, for example, may be prepared by mixing theformulation with excipients intended to add binding qualities todisintegration qualities. The mixture is either directly compressed, orgranulated and then compressed using methods and machinery known tothose in the pharmaceutical compounding industry. The resultantcompressed tablet dosage units are then packaged according to marketneed, for example, in unit dose, rolls, bulk bottles, blister packs,etc.

The present technology also contemplates the use ofbiologically-acceptable carriers which may be prepared from a wide rangeof materials. Without being limited to, such materials include diluents,binders and adhesives, lubricants, plasticizers, disintegrants,colorants, bulking substances, flavorings, sweeteners and miscellaneousmaterials such as buffers and adsorbents in order to prepare aparticular medicated composition.

Binders may be selected from a wide range of materials such ashydroxypropylmethylcellulose, ethylcellulose, or other suitablecellulose derivatives, povidone, acrylic and methacrylic acidco-polymers, pharmaceutical glaze, gums, milk derivatives, such as whey,starches, and derivatives, as well as other conventional binders knownto persons working in the art. Exemplary non-limiting solvents arewater, ethanol, isopropyl alcohol, methylene chloride or mixtures andcombinations thereof. Exemplary non-limiting bulking substances includesugar, lactose, gelatin, starch, silicon dioxide, and derivativesthereof.

It should be understood that in addition to the ingredients particularlymentioned above, the formulations of the present technology can includeother suitable agents such as flavoring agents, preservatives andantioxidants, among others. Such antioxidants are preferably foodacceptable and could include, for example, vitamin E, carotene, BHT orother antioxidants or derivatives thereof.

Other compounds, which may be included in the compositions, compounds,conjugates, formulations and/or prodrugs of the present technology, byadmixture are, for example, medically inert ingredients, e.g., solid andliquid diluents, such as lactose, dextrose, saccharose, cellulose,starch or calcium phosphate for tablets or capsules, olive oil or ethyloleate for soft capsules and water or vegetable oil for suspensions oremulsions; lubricating agents such as silica, talc, stearic acid,magnesium or calcium stearate and/or polyethylene glycols; gellingagents such as colloidal clays; thickening agents such as gum tragacanthor sodium alginate, binding agents such as starches, arabic gums,gelatin, methylcellulose, carboxymethylcellulose orpolyvinylpyrrolidone; disintegrating agents such as starch, alginicacid, alginates or sodium starch glycolate; effervescing mixtures;dyestuff; sweeteners; wetting agents such as lecithin, polysorbates orlaurylsulfates; or other therapeutically acceptable accessoryingredients, such as humectants, preservatives, buffers andantioxidants, which are known additives for such formulations.

For oral administration of various embodiments of the presenttechnology, fine powders or granules containing comminuting, diluting,dispersing and/or surface-active agents may be presented in a draught,in water or a syrup, in capsules or sachets in the dry state, in anon-aqueous suspension wherein suspending agents may be included, or ina suspension in water or a syrup. Where desirable, flavoring,preserving, suspending, thickening or emulsifying agents can also beincluded.

Liquid dispersions for oral administration may be syrups, emulsions orsuspensions. The syrups may contain as carrier, for example, saccharoseor saccharose with glycerol and/or mannitol and/or sorbitol. Inparticular, a syrup for diabetic patients can contain as carriers onlyproducts, for example sorbitol, which do not metabolize to glucose orwhich metabolize only a very small amount to glucose. The suspensionsand the emulsions may contain a carrier, for example a natural gum,agar, sodium alginate, pectin, methylcellulose, carboxymethylcellulosepolyvinyl alcohol, or derivatives or combinations thereof.

Formulations of oxymorphone of the present technology can be, forexample, combination therapies of oxymorphone and one or more othernon-narcotic active ingredient depending on intended indication oroff-label usage/application. Examples of these active pharmaceuticalsinclude, but are not limited to, acetaminophen, phenylpropanolamine,homatropine, ibuprofen, aspirin, pheniramine, chlorpheniramine,phenylephrine, pseudoephedrine, pyrilamine, guaifenesin, and derivativesand combinations thereof. The conjugated oxymorphone of the presenttechnology can be formulated with one or a combination of these or otheractive substances, among others, or as standalone active ingredientwithout any other actives.

The conjugates, compounds, compositions, formulations, and/or prodrugsof the present technology may be used in methods of treating a patient(human or animal) having a disease, disorder or condition requiring ormediated by binding or inhibiting binding of an opioid to the opioidreceptors of the patient. Treatment comprises the step orallyadministering to the patient a therapeutically effective amount of atleast one conjugate, compound, composition, prodrug, or formulation ofoxymorphone as described in the present technology. The conjugate canexhibit a slower rate of release over time and AUC when compared to anequivalent molar amount of unconjugated oxymorphone. In otherembodiments, at least one conjugate, compound, composition, prodrug, orformulation of the present technology can exhibit less variability inthe oral PK profile when compared to unconjugated oxymorphone.

In other embodiments, at least one oxymorphone conjugate, compound,composition, prodrug, or formulation of the present technology isprovided in an amount sufficient to provide a therapeutically equivalentAUC (area under the curve) when compared to a molar equivalent amount ofunconjugated oxymorphone. In further embodiments, the oxymorphoneconjugate, composition, compound, formulation, or prodrug of the presenttechnology is provided in an amount sufficient to provide atherapeutically equivalent AUC when compared to unconjugated oxymorphonebut has a lower C_(max) (peak concentration) in plasma or does notprovide an equivalent C_(max) in plasma concentrations. In some aspects,the conjugate, composition, compound, formulation, or prodrug of thepresent technology is provided in an amount sufficient to provide atherapeutically equivalent C_(max) when compared to unconjugatedoxymorphone.

Suitable diseases, disorders or conditions that can be treated by theprodrugs or compositions of the present technology are narcoticaddiction or drug addiction and/or acute or chronic pain, among others.

The prodrugs, compositions, compounds, conjugates, or formulations ofthe present technology can be, without limitation, prepared in oraldosage forms. These dosage forms include but are not limited to tablet,capsule, caplet, troche, lozenge, powder, suspension, syrup, solution ororal thin film (OTF). Example oral administration forms are capsule,tablet, solutions and OTF. Solid dosage forms can include the followingtypes of excipients: antiadherents, binders, coatings, disintegrants,fillers, flavors and colors, glidants, lubricants, preservatives,sorbents and sweeteners. Other formulations of oxymorphone are tablets,capsules, modified release capsules, extended release tablets,controlled release capsules, suppository, powder for injection, oralliquid, cough syrup, and injections.

Dosages for the conjugates of the present technology depend on theirmolecular weight and the respective weight-percentage of oxymorphone aspart of the whole conjugate, and therefore can be higher than thedosages of free oxymorphone. Oral dosage strengths based on oxymorphonehydrochloride range from about 5 mg to about 10 mg for immediate releaseformulations and from about 5 mg to about 40 mg for extended releaseformulations. Doses should be titrated to appropriate analgesic effectswhile minimizing adverse effects. Some example doses include, withoutlimitation, 5, 7.5, 10, 15, 20, 30, 40 mg. Dosages for the conjugates ofthe present technology can be higher depending on their molecular weightand the respective weight-percentage of oxymorphone as part of the wholeconjugate. Dose conversion from oxymorphone hydrochloride to oxymorphoneprodrug can be performed using the following formula:

${{dose}\left( {{OM}\mspace{14mu} {prodrug}} \right)} = {f_{BA} \times {{dose}\left( {{OM} \cdot {HCl}} \right)} \times \frac{{MW}\left( {{OM}\mspace{14mu} {prodrug}} \right)}{337.8\frac{g}{mol}}}$

OM=oxymorphoneHCl=hydrochlorideMW=molecular weightf_(BA)=correction factor accounting for differences in bioavailabilitybetween unmodified oxymorphone and prodrugs or conjugates of thisinvention.

Suitable exemplar dosages of the conjugated oxymorphone of the presenttechnology include, but are not limited to, formulations including fromabout 0.5 mg or higher, alternatively from about 2.5 mg or higher,alternatively from about 5.0 mg or higher, alternatively from about 7.5mg or higher, alternatively from about 10 mg or higher, alternativelyfrom about 20 mg or higher, alternatively from about 30 mg or higher,alternatively from about 40 mg or higher, alternatively from about 50 mgor higher, alternatively from about 60 mg or higher, alternatively fromabout 70 mg or higher, alternatively from about 80 mg or higher,alternatively from about 90 mg or higher, alternatively from about 100mg or higher, and include any additional increments thereof, forexample, about 0.1, about 0.2, about 0.25, about 0.3, about 0.4, about0.5, about 0.6, about 0.7, about 0.75, about 0.8, about 0.9 or about 1.0mg and multiplied factors thereof, (e.g., ×2, ×2.5, ×5, ×10, ×100,etc.). The present technology also includes dosage formulationsincluding currently approved formulations of oxymorphone, where thedosage can be calculated using the above-noted formula determined by theamount of oxymorphone hydrochloride. The present technology provides fordosage forms formulated as a single therapy or as a combination therapywith other active pharmaceutical ingredients.

The conjugates of oxymorphone with derivatives of NSAID of the presenttechnology have a number of advantages including, but not limited to, areduced patient variability of plasma concentrations of oxymorphone whencompared to free oxymorphone, reduced drug abuse potential, reduced riskof chemical or physical manipulation resulting in full dosage ofoxymorphone released, improved dosage forms through covalent linkage toaryl carboxylic acids or derivatives thereof, increased or decreasedmetabolism of oxymorphone and/or decreased side-effects other than drugabuse.

Side effects of opioid analgesics include gastrointestinal dysfunctioncaused by the opioids binding to the mu (μ) receptors present in thegastrointestinal tract. The side-effects in the stomach can include areduction in the secretion of hydrochloric acid, decreased gastricmotility, thus prolonging gastric emptying time, which can result in,for example, esophageal reflux. Passage of the gastric contents throughthe duodenum may be delayed by as much as 12 hours, and the absorptionof orally administered drugs is retarded. In the small intestines, theopioid analgesics diminish biliary, pancreatic and intestinal secretionsand delay digestion of food in the small intestine. Propulsiveperistaltic waves in the colon are diminished or abolished afteradministration of opioids, and tone is increased to the point of spasm.The resulting delay in the passage of bowel contents causes considerabledesiccation of the feces, which, in turn retards their advance throughthe colon. These actions, combined with inattention to the normalsensory stimuli for defecation reflex due to the central actions of thedrug, contribute to opioid-induced constipation or “OIC.”

Oxymorphone is used for the treatment of moderate to severe pain. Theprodrugs of the present technology may be administered for the relief ofpain or for the treatment of any condition that may require the blockingof opioid receptors. The conjugates of the present technology canprovide a decrease in side effects of the opioid analgesic, includingreduced or inhibited constipatory effects.

The present technology also provides a method of synthesis for thepreparation of the conjugated oxymorphone of the present technology. Inone embodiment, the synthesis of the present technology includes thesteps of: protection of the ligand, if necessary; activation of theligand carboxylic acid group, if not already in activated form; additionof the activated ligand to oxymorphone or vice versa in the presence ofbase; and removal of ligand protecting groups, if applicable.

If the aryl carboxylic acid contains any additional reactive functionalgroups that may interfere with the coupling to oxymorphone, it may benecessary to first attach one or more protecting groups. Any suitableprotecting group may be used depending on the type of functional groupand reaction conditions. Some protecting group examples are: acetyl(Ac), β-methoxyethoxymethyl ether (MEM), methoxymethyl ether (MOM),p-methoxybenzyl ether (PMB), trimethylsilyl (TMS),tert.-butyldimethylsilyl (TBDPS), triisopropylsilyl (TIPS),carbobenzyloxy (Cbz), p-methoxybenzyl carbonyl (Moz),tert.-butyloxycarbonyl (Boc), 9-fluorenylmethyloxycarbonyl (Fmoc),benzyl (Bn), p-methoxybenzyl (MPM), tosyl (Ts). Temporary formation ofacetals or ketals from carbonyl functions may also be appropriate.

The carboxylic acid group of the ligands should be activated in order toreact with oxymorphone and to generate appreciable amounts of conjugate.This activation can be accomplished in numerous ways by a variety ofcoupling agents known to one skilled in the art. Examples of suchcoupling agents are: N,N-dicyclohexylcarbodiimide (DCC),N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide (EDCI),N,N′-diisopropylcarbodiimide (DIC), 1,1′-carbonyldiimidazole (CDI) orother carbodiimides;(benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate(BOP), bromotripyrrolidinophosphonium hexafluorophosphate (PyBroP),(benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate(PyBOP) or other phosphonium-based reagents;O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate(HBTU), O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumtetrafluoroborate (TBTU), fluoro-N,N,N′,N′-tetramethylformamidiniumhexafluorophosphate (TFFH),N,N,N′,N′-tetramethyl-O—(N-succinimidyl)uronium tetrafluoroborate (TSTU)or other aminium-based reagents. The aryl carboxylic acid can also beconverted to a suitable acyl halide, acyl azide or mixed anhydride.

A base may be required at any step in the synthetic scheme of an arylcarboxylic acid conjugate of oxymorphone. Suitable bases include but arenot limited to: 4-methylmorpholine (NMM), 4-(dimethylamino)pyridine(DMAP), N,N-diisopropylethylamine, lithium bis(trimethylsilyl)amide,lithium diisopropylamide (LDA), any alkali metal tert.-butoxide (e.g.,potassium tert.-butoxide), any alkali metal hydride (e.g., sodiumhydride), any alkali metal alkoxide (e.g., sodium methoxide),triethylamine or any other tertiary amine.

Suitable solvents that can be used for any reaction in the syntheticscheme of an aryl carboxylic acid conjugate of oxymorphone include butare not limited to: acetone, acetonitrile, butanol, chloroform,dichloromethane, dimethylformamide (DMF), dimethylsulfoxide (DMSO),dioxane, ethanol, ethyl acetate, diethyl ether, heptane, hexane,methanol, methyl tert.-butyl ether (MTBE), isopropanol, isopropylacetate, diisopropyl ether, tetrahydrofuran, toluene, xylene or water.

In some embodiments, the prodrug is hydrophobic and thus poorly watersoluble. This results in a gel-like consistency or clumpy suspensionwhen the compound is mixed with water. Not to be bound by any theory, itis believed that these compounds would also congeal or become clumpywhen a human subject (or animal subject) tries to inhale themintranasally (“snorting”). This property would not only make an attemptof intranasal abuse an unpleasant experience but would likely alsoprevent the prodrug from permeating the nose mucosa. As a consequence,these compounds become ineffective for this route of administration.

The present technology also provides for pharmaceutical kits for thetreatment or prevention of drug withdrawal symptoms or pain in a patient(human or animal). The patient may be a human or animal patient.Suitable human patients include, for example, pediatric patients,geriatric (elderly) patients, and normative patients. In at least oneembodiment, the kit comprises a specific amount (see exemplary amountspresented below, however, it should be appreciated by those skilled inthe art are non-exhaustive and other amounts are also envisageddepending upon the patient to be treated or condition, disease, ordisorder to be addressed) of the individual doses in a packagecontaining a pharmaceutically effective amount of at least one conjugateof oxymorphone of the present technology. The kit can further includeinstructions for use of the kit. The instructions can be directed to theuse of said conjugate in a dosage range of between about 0.5 mg to about200 mg per dose, including about 1 mg, about 2 mg, about 3 mg, about 4mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, about 10mg, about 11 mg, about 12 mg, about 13 mg, about 14 mg, about 15 mg,about 16 mg, about 17 mg, about 18 mg, about 19 mg, about 20 mg, about21 mg, about 22 mg, about 23 mg, about 24 mg, about 25 mg, about 26 mg,about 27 mg, about 28 mg, about 29 mg, about 30 mg, about 31 mg, about32 mg, about 33 mg, about 34 mg, about 35 mg, about 36 mg, about 37 mg,about 38 mg, about 39 mg, about 40 mg, about 41 mg, about 42 mg, about43 mg, about 44 mg, about 45 mg, about 46 mg, about 47 mg, about 48 mg,about 49 mg, about 50 mg, about 51 mg, about 52 mg, about 53 mg, about54 mg, about 55 mg, about 56 mg, about 57 mg, about 58 mg, about 59 mg,about 60 mg, about 61 mg, about 62 mg, about 63 mg, about 64 mg, about65 mg, about 66 mg, about 67 mg, about 68 mg, about 69 mg, about 70 mg,about 71 mg, about 72 mg, about 73 mg, about 74 mg, about 75 mg, about76 mg, about 77 mg, about 78 mg, about 79 mg, about 80 mg, about 81 mg,about 82 mg, about 83 mg, about 84 mg, about 85 mg, about 86 mg, about87 mg, about 88 mg, about 89 mg, about 90 mg, about 91 mg, about 91 mg,about 92 mg, about 93 mg, about 94 mg, about 95 mg, about 96 mg, about97 mg, about 98 mg, about 99 mg, about 100 mg, about 101 mg, about 102mg, about 103 mg, about 104 mg, about 105 mg, about 106 mg, about 107mg, about 108 mg, about 109 mg, about 110 mg, about 111 mg, about 112mg, about 113 mg, about 114 mg, about 115 mg, about 116 mg, about 117mg, about 118 mg, about 119 mg, about 120 mg, about 121 mg, about 122mg, about 123 mg, about 124 mg, about 125 mg, about 126 mg, about 127mg, about 128 mg, about 129 mg, about 130 mg, about 131 mg, about 132mg, about 133 mg, about 134 mg, about 135 mg, about 136 mg, about 137mg, about 138 mg, about 139 mg, about 140 mg, about 141 mg, about 142mg, about 143 mg, about 144 mg, about 145 mg, about 146 mg, about 147mg, about 148 mg, about 149 mg, about 150 mg, about 151 mg, about 152mg, about 153 mg, about 154 mg, about 155 mg, about 156 mg, about 157mg, about 158 mg, about 159 mg, about 160 mg, about 161 mg, about 162mg, about 163 mg, about 164 mg, about 165 mg, about 166 mg, about 167mg, about 168 mg, about 169 mg, about 170 mg, about 171 mg, about 172mg, about 173 mg, about 174 mg, about 175 mg, about 176 mg, about 177mg, about 178 mg, about 179 mg, about 180 mg, about 181 mg, about 182mg, about 183 mg, about 184 mg, about 185 mg, about 186 mg, about 187mg, about 188 mg, about 189 mg, about 190 mg, about 191 mg, about 191mg, about 192 mg, about 193 mg, about 194 mg, about 195 mg, about 196mg, about 197 mg, about 198 mg, about 199 mg, and about 200 mg per dose.

The specified amount of individual doses may contain from about 1 toabout 100 individual dosages, alternatively from about 1 to about 60individual dosages, alternatively from about 10 to about 30 individualdosages, including, about 1, about 2, about 5, about 10, about 15, about20, about 25, about 30, about 35, about 40, about 45, about 50, about55, about 60, about 70, about 80, about 100, and include any additionalincrements thereof, for example, 1, 2, 5, 10 and multiplied factorsthereof, (e.g., ×2, ×2.5, ×5, ×10, ×100, etc).

The presently described technology and its advantages will be betterunderstood by reference to the following examples. These examples areprovided to describe specific embodiments of the present technology. Byproviding these specific examples, it is not intended limit the scopeand spirit of the present technology. It will be understood by thoseskilled in the art that the full scope of the presently describedtechnology encompasses the subject matter defined by the claimsappending this specification, and any alterations, modifications, orequivalents of those claims.

It will be understood by those skilled in the art that the full scope ofthe presently described technology encompasses the subject matterdefined by the claims appending this specification, and any alterations,modifications, or equivalents of those claims. It is to be understoodthat the foregoing describes preferred embodiments of the technology andthat modifications may be made therein without departing from the spiritor scope of the invention as set forth in the appended claims.

EXAMPLES Example 1: Oral PK Profiles of Conjugated Oxymorphone of thePresent Technology

Oral PK curves were determined for a number of prodrug conjugates of thepresent technology. Rats were orally administered at an amount of theconjugate equivalent to 2 mg/kg of freebase oxymorphone and the plasmaconcentrations of released oxymorphone were measured over time byLC-MS/MS. The results are tabulated in the following Table 1:

TABLE 1 RELATIVE ORAL PK PARAMETERS C_(max) AUC Conjugate [ng/mL] [h ×ng/mL] T_(max) [h] %-C_(max) %-AUC %-T_(max) 6-Bz-OM 6.4 15.0 1.80 67 78129 3-Cinnamate-OM 19.0 36.8 1.50 236 190 136 3,6-(Cinnamate)₂-OM 8.714.5 0.75 43 38 50 3-(4-MeO-Bz)-OM 23.6 43.2 1.05 99 100 1003-(2-OH-Bz)-OM 17.5 31.3 0.65 74 72 62 6-(2-OH-Bz)-OM 31.6 50.6 0.75 157134 60 3-ABz-OM 17.7 25.0 0.44 nd nd nd 2-ABz-OM 24.2 33.7 0.45 nd nd nd4-OH-Bz-OM 22.9 25.9 0.85 58 64 106 3-Vanillate-OM 7.5 14.7 0.80 97 9246 6-Vanillate-OM 5.0 8.9 1.70 65 56 97 6-(4-MeO-Bz)-OM 8.6 12.2 0.25 9069 22 3,6-(4-MeO-Bz)₂-OM 10.6 26.0 0.25 121 110 35 6-(3-ABz)-OM 6.2 16.71.90 32 46 276 6-Cinnamate-OM 11.4 28.0 1.55 59 77 225 3-(2-AcO-Bz)-OM15.8 22.5 0.25 78 72 25 3-Ketoprofen-OM 30.3 49.7 0.30 150 159 303-Fenoprofen-OM 9.6 14.8 0.60 52 59 100 3-Diflunisal-OM 13.2 17.6 0.8552 85 340 6-Ketoprofen-OM 11.8 20.6 0.65 47 99 260 6-Diflunisal-OM 50.667.2 0.25 nd nd nd OM: Oxymorphone AUC: Area Under the Curve C_(max):Peak Plasma Concentration T_(max): Time to Peak Plasma Concentration nd:no data

The PK profile graphs from the oral rat (Sprague-Dawley rats) studycomparing oxymorphone plasma concentrations generated by oxymorphone,6-Bz-OM, and 3-Indomethacin-OM are shown in FIG. 14.

The PK profile graphs from the oral rat (Sprague-Dawley rats) studycomparing oxymorphone plasma concentrations generated by oxymorphone,and 3,6-(Cinnamate)₂-OM are shown in FIG. 15.

The PK profile graphs from the oral rat (Sprague-Dawley rats) studycomparing oxymorphone plasma concentrations generated by oxymorphone,6-Bz-OM, and 3-Indomethacin-OM are shown in FIG. 16.

The PK profile graphs from the oral rat (Sprague-Dawley rats) studycomparing oxymorphone plasma concentrations generated by oxymorphone,3-(4-MeO-Bz)-OM, and 3-(2-OH-Bz)-OM are shown in FIG. 17.

The PK profile graphs from the oral rat (Sprague-Dawley rats) studycomparing oxymorphone plasma concentrations generated by oxymorphone,6-(2-OH-Bz)-OM, and 6-(4-OH-Bz)-OM are shown in FIG. 18.

The PK profile graphs from the oral rat (Sprague-Dawley rats) studycomparing oxymorphone plasma concentrations generated by oxymorphone and3-(4-OH-Bz)-OM are shown in FIG. 19.

The PK profile graphs from the oral rat (Sprague-Dawley rats) studycomparing oxymorphone plasma concentrations generated by oxymorphone,3-Vanillate-OM, and 6-Vanillate-OM are shown in FIG. 20.

The PK profile graphs from the oral rat (Sprague-Dawley rats) studycomparing oxymorphone plasma concentrations generated by oxymorphone,6-(4-OH-Bz)-OM, and 3,6-(4-MeO-Bz)₂-OM are shown in FIG. 21.

The PK profile graphs from the oral rat (Sprague-Dawley rats) studycomparing oxymorphone plasma concentrations generated by oxymorphone,6-(3-ABz)-OM, and 6-(Cinnamate)-OM are shown in FIG. 22.

The PK profile graphs from the oral rat (Sprague-Dawley rats) studycomparing oxymorphone plasma concentrations generated by oxymorphone,3-(2-OAc-Bz)-OM, and 2-Ketoprofen-OM are shown in FIG. 23.

The PK profile graphs from the oral rat (Sprague-Dawley rats) studycomparing oxymorphone plasma concentrations generated by oxymorphone,and 3-Fenoprofen-OM are shown in FIG. 24.

The PK profile graphs from the oral rat (Sprague-Dawley rats) studycomparing oxymorphone plasma concentrations generated by oxymorphone,3-Difluonisal-OM, and 6-Ketoprofen-OM are shown in FIG. 25.

The Examples of oxymorphone prodrugs have shown similar oralbioavailability (systemic absorption) with respect to oxymorphone (OM)compared to unconjugated OM.

The examples provided in the presently claimed technology illustrate theeffective release of the active ingredient, OM, from several newchemical entity prodrugs discovered by the inventors. Plasmaconcentrations of OM following oral administration of these OM prodrugsto rats produced variable levels of exposure compared to the plasmaconcentrations produced by unconjugated OM. In some case, oralbioavailability of the active ingredient, OM, was improved by theprodrug.

All PK parameters from the above experiments were calculated andexpressed as % change from the control (OM). These PK parametersincluded maximal plasma concentration (C_(max)), area under curve (AUC),and time at which C_(max) occurred (T_(max)). These parameters are shownin Table 1 relative to the OM controls.

Example 2: Intranasal PK Profiles of Conjugated Oxymorphone of thePresent Technology

Intranasal PK curves were determined for a number of prodrug conjugatesof the present technology. Rats were intranasally administered at anamount of the conjugate equivalent to 0.2 mg/kg of freebase oxymorphoneand the plasma concentrations of released oxymorphone were measured overtime by LC-MS/MS.

OM is often insufflated because this route of administration producesrapid onset and high levels of euphoria. This can be explained by theintranasal (IN) pharmacokinetics. Intranasally delivered OM produceshigh plasma concentrations (C_(max)) of OM very quickly (short T_(max)).It also results in the highest OM exposure levels (AUC). Alternatively,insufflation of our abuse deterrent OM prodrugs produces drasticallylowers plasma concentrations of OM, delays T_(max) and often leads tovery low OM exposure. Some examples of these characteristics areprovided in FIGS. 26-29.

Non oral routes of delivery bypass the activation step required for theoxymorphone prodrugs to release sufficient levels of oxymorphone,imparting abuse deterrence via, for example, intranasal and intravenousadministration.

Intranasal pharmacokinetics was studied compared to OM in rats. Farlower plasma concentrations of OM were observed for the prodrugsdemonstrating good intranasal abuse deterrence potential.

Intranasal PK parameters that are often associated with abuse potential(C_(max) and T_(max)) were changed (decreased and increased,respectively) for many OM prodrugs such that their abusability wouldpredictively be much lower.

All PK parameters from the above experiments were calculated andexpressed as % change from the control (OM). These PK parametersincluded maximal plasma concentration (C_(max)), area under curve (AUC),and time at which Cmax occurred (T_(max)). These parameters are shown inTable 2 relative to the OM controls.

TABLE 2 Relative Intranasal (IN) PK Parameters AUC T_(max) ConjugateC_(max) [ng/mL] [h × ng/mL] [h] %-C_(max) %-AUC %-T_(max) 6-Bz-OM 145.235.1 0.08 36 42 100 3-(4-MeO-Bz)-OM 244.9 63.1 0.08 61 76 1003-(2-OH-Bz)-OM 276.1 65.9 0.08 55 66 100 4-OH-Bz-OM 364.4 88.1 0.08 7388 100 3-Diflunisal-OM 151.5 108.2 0.17 41 131 200 6-Diflunisal-OM 39.120.7 0.08 11 25 100 3,6-(4-MeO-Bz)₂-OM 33.5 24.6 0.14 9 30 167

Example 3: Comparison Tests

The presently claimed technology utilizes covalent conjugation of anopioid, oxymorphone, with various aryl carboxylic acids to reduce thepotential for causing overdose or abuse by requiring the activepharmaceutical ingredient (API), oxymorphone, to be released in vivoafter oral administration. These conjugates are intended to be prodrugsof the known-safe, but highly abused, parent molecules. To fulfill thegenerally accepted definition of a prodrug, the conjugate must not havesignificant pharmacological activity and only become effective afterrelease of the active moiety in vivo.

The presently described technology relates to oxymorphone conjugatesthat may appear structurally similar to examples in previously describedtechnologies but their properties are profoundly different and notobvious. To illustrate this, the oral pharmacokinetic (PK) profiles ofsome of the presently claimed conjugates of oxymorphone are plottedagainst structurally similar conjugates of hydrocodone, hydromorphoneand oxycodone.

The plasma concentration measurement of each opioid released from aconjugate was normalized to the corresponding maximum plasmaconcentration (C_(max)) of its parent opioid at an equimolar dose (i.e.,C_(max) of the parent opioid was set to 100%). The resulting PK curvesshow plasma concentrations of the opioids released from variousconjugates plotted as percent of peak plasma concentration (C_(max)) ofeach respective parent opioid. This facilitates the comparison of theopioid concentrations produced by several conjugates of differentopioids conjugated with the same carboxylic acid.

For example, FIG. 30 compared three benzoic acid conjugates ofoxymorphone with a similar conjugate of hydrocodone. While thehydrocodone conjugate produced similar released opioid plasmaconcentrations as its parent opioid (hydrocodone bitartrate), bothoxymorphone conjugates exhibited blunted released opioid plasmaconcentrations compared to their parent opioid (oxymorphonehydrochloride).

FIG. 31 compared two oxymorphone prodrugs conjugated with4-methoxybenzoic acid conjugates to one hydrocodone conjugated with thesame acid. In this example, the hydrocodone conjugate exhibited a higheropioid release compared to both oxymorphone conjugates despitehydrocodone being covalently bound to the same acid as the oxymorphoneconjugates. Interestingly, the oxymorphone conjugates also had uniquepharmacokinetic characteristics.

FIG. 32 shows the relative PK profiles of cinnamic acid conjugates ofoxymorphone and hydrocodone. Again, the release profiles of the twodifferent opioids were very different and unexpected.

FIG. 33 illustrates the PK profiles of 4-methoxybenzoic acid conjugatedoxymorphone and hydromorphone at the same position on each opioidmolecule. Despite having identical ligand groups attached at the samepositions, the hydromorphone conjugate released more opioid compared tothe oxymorphone conjugates. Similarly, FIG. 34 compared oxymorphoneprodrugs with hydromorphone prodrugs. FIGS. 35 through 38 comparedoxymorphone prodrugs with oxycodone prodrugs with various ligandmoieties attached, matched by graph.

The PK profile data graphs from the presently described technology isnow described in such full, clear, concise and exact terms as to enableany person skilled in the art to which it pertains, to practice thesame. It is to be understood that the foregoing describes preferredembodiments of the technology and that modifications may be made thereinwithout departing from the spirit or scope of the invention as set forthin the appended claims.

1. A compound having the following structure

or a salt of said compound.
 2. A composition comprising a conjugate,wherein the conjugate is the compound of claim 1, a salt thereof, or acombination thereof.
 3. The composition of claim 2, wherein thecomposition is in a dosage form selected from the group consisting of atablet, a capsule, a caplet, a soft gel, a suppository, a troche, alozenge, an oral powder, a solution, an oral film, a thin strip, aslurry, and a suspension.
 4. The composition of claim 2, wherein thecomposition is in an amount sufficient to provide a therapeuticallyequivalent AUC when compared to unconjugated oxymorphone whenadministered orally.
 5. The composition of claim 2, wherein thecomposition is in an amount sufficient to provide a therapeuticallyequivalent AUC and C_(max) when compared to an equivalent molar amountof unconjugated oxymorphone when administered orally.
 6. The compositionof claim 2, wherein the composition is in an amount sufficient toprovide a therapeutically equivalent AUC and a lower C_(max) whencompared to an equivalent molar amount of unconjugated oxymorphone whenadministered orally.
 7. The composition of claim 2, wherein intranasalor intravenous administration of the compound provides a lower AUCand/or Cmax when compared to an equivalent molar amount of unconjugatedoxymorphone.
 8. The composition of claim 2, wherein oral administrationof the compound provides a decreased overdose potential when compared toan equivalent molar amount of unconjugated oxymorphone.
 9. Thecomposition of claim 2, wherein the compound provides an increasedtamper resistance when compared to unconjugated oxymorphone.
 10. Amethod for treating pain in a patient, said method comprising the stepof selecting a patient in need thereof and orally administering to thepatient a therapeutically effective amount of at least one compositionof claim
 2. 11. The method of claim 10, wherein the pain is selectedfrom the group consisting of acute pain, chronic pain, moderate pain,severe pain, and moderately severe pain.
 12. The method of claim 10,wherein the patient is human or animal.
 13. The composition of claim 2,wherein the composition has reduced side effects when compared withunconjugated oxymorphone.
 14. The composition of claim 13, wherein thereduced side effects comprise gastrointestinal dysfunction, wherein thegastrointestinal dysfunction comprises constipation, decreasedhydrochloric acid secretion in the stomach, decreased gastric motility,esophageal reflux, or combinations thereof.
 15. The composition of claim2, wherein the conjugate is a pharmaceutically acceptable anionic saltform, cationic salt form, or salt mixture thereof.
 16. The compositionof claim 15, wherein the anionic salt form is selected from the groupconsisting of an acetate, L-aspartate, besylate, bicarbonate, carbonate,D-camsylate, L-camsylate, citrate, edisylate, formate, fumarate,gluconate, hydrobromide/bromide, hydrochloride/chloride, D-lactate,L-lactate, D,L-lactate, D,L-malate, L-malate, mesylate, pamoate,phosphate, succinate, sulfate, bisulfate, D-tartrate, L-tartrate,D,L-tartrate, meso-tartrate, benzoate, gluceptate, D-glucuronate,hybenzate, isethionate, malonate, methylsufate, 2-napsylate, nicotinate,nitrate, orotate, stearate, tosylate, thiocyanate, acefyllinate,aceturate, aminosalicylate, ascorbate, borate, butyrate, camphorate,camphocarbonate, decanoate, hexanoate, cholate, cypionate,dichloroacetate, edentate, ethyl sulfate, furate, fusidate, galactarate,galacturonate, gallate, gentisate, glutamate, glutarate,glycerophosphate, heptanoate, hydroxybenzoate, hippurate,phenylpropionate, iodide, xinafoate, lactobionate, laurate, maleate,mandelate, methanesufonate, myristate, napadisilate, oleate, oxalate,palmitate, picrate, pivalate, propionate, pyrophosphate, salicylate,salicylsulfate, sulfosalicylate, tannate, terephthalate, thiosalicylate,tribrophenate, valerate, valproate, adipate, 4-acetamidobenzoate,camsylate, octanoate, estolate, esylate, glycolate, thiocyanate, andundecylenate, or mixtures thereof.
 17. The composition of claim 15,wherein the cationic salt form is selected from the group consisting ofsodium, potassium, calcium, magnesium, zinc, aluminum, lithium,cholinate, lysinium, ammonium, tromethamine, or mixtures thereof. 18.The composition of claim 2, wherein the compound is present in an amountper unit dose of between about 1 mg and about 100 mg per unit dosewherein the amount per unit dose is based on the content of oxymorphone.19. The composition of claim 2, wherein the composition is formulatedfor oral administration, suppository administration, powder forinjection, or intrathecal administration.
 20. The composition of claim19, wherein the composition formulated for oral administration is atablet, a granule, a capsule, a soft gel, a caplet, a pill, an oralpowder, a troche, a lozenge, a slurry, a solution, a suspension, anemulsion, an elixir, or an oral thin film (OTF).
 21. The composition ofclaim 20, wherein the composition is formulated in a tablet form, asolution, a suspension, or a soft gel form.
 22. The composition of claim21, wherein the tablet form further comprises one or more excipients,wherein the excipients are selected from the group consisting ofanti-adherents, binders, coatings, disintegrants, fillers, flavors,dyes, colors, glidants, lubricants, preservatives, sorbents, sweeteners,derivatives thereof, and combinations thereof.
 23. The composition ofclaim 22, wherein the binder is selected from the group consisting ofhydroxypropylmethylcellulose, ethyl cellulose, povidone, acrylic andmethacrylic acid co-polymers, pharmaceutical glaze, gums, and milkderivatives.
 24. The composition of claim 2, wherein the compositionexhibits an improved AUC and rate of release over time when compared tounconjugated oxymorphone over the same time period when administeredorally.
 25. The composition of claim 2, wherein the composition exhibitsless patient variability in the oral PK profile when compared tounconjugated oxymorphone.
 26. The composition of claim 2, wherein thecomposition is in an amount sufficient to provide a therapeuticallyequivalent AUC when compared to unconjugated oxymorphone whenadministered non orally.